N substituted piperidine compounds

ABSTRACT

IN WHICH Q IS O OR S AND R4 IS H, CH3 OR PHENYL, AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF ARE USEFUL AS PSYCHOTROPIC AGENTS FOR THE TREATMENT OF SCHIZOPHRENIA, PSYCHONEUROSIS, MANIC-DEPRESSIVE PSYCHOSIS AND THE LIKE.   &gt;C&lt;(-NH-CO-N(-CH3)-CO-), AND &gt;C&lt;(-NH-CO-CH(-R4)-Q-)   IN WHICH R2 IS OH, CN, CONH2, COOC2H5 OR COCH3 AND R3 IS DIMETHYLAMINO, PIPERIDINO, MORPHOLINO, PHENYL SUBSTITUTED PHENYL (THE SUBSTITUENT BEING CL, CH3 OR CF3) OR ACETYLAMINO,   &gt;C(-R2)-R3   WHEREIN Y IS O, S OR SO2, R1 IS H, CL, CH3 OR OCH3 AND Z IS A BIVALENT GROUP SELECTED FROM THE GROUP CONSISTING OF   Y-(4-R1-1,2-PHENYLENE)-)   (-(CH2)2-Z-(CH2)2-)&gt;N-(CH2)2-CH=C&lt;(-(1,2-PHENYLENE)-CH2-   N-SUBSTITUTED PIPERIDINE COMPOUNDS OF THE FORMULA

United States Patent O E 3,770,729 N-SUBSTITUTED PIPERIDINE COMPOUNDS Michio Nakanishi, Oita, and Takanori e and Chiaki Tashiro, Yoshitomi-machi, Japan, assignors to Yoshitomi Pharmaceutical Industries, Ltd., Osaka, Japan No Drawing. Filed Dec. 21, 1971, Ser. No. 210,592 5 Claims priority, application Japan, Dec. 22, 1970,

45/117,048; Dec. 25, 1970, 45/128,281; Dec. 28, 1970, 46/127,144

Int. Cl. C07d 29/28 US. Cl. 260-440 TC ABSTRACT OF THE DISCLOSURE N-substituted piperidine compounds of the formula wherein Y is o, s or $0 R is H, 01, CH, or OCH, and Z is a bivalent group selected from the group consisting in which is OH, CN, CONH cooc ri or cocH and R is dimethylamino, piperidino, morpholino, phenyl substituted phenyl (the substituent being Cl, CH or CR or acetylamino,

useful as psychotropic agents for the treatment of schizophrenia, psychoneurosis, manic-depressive psychosis and the like.

PRIOR ART In our copending application, filed Jan. 7,' 1971, Ser. No. 104,770, there are disclosed compounds of formula Yiw 3,770,729 Patented Nov. 6, 1973 and pharmaceutically acceptable acid addition salts thereof, wherein X is H, Cl, CH CF OCH or SCH each of Y and Y is H or Y and Y combinedly represent -CH -CH --CH=CH-, -C(CH 0- or S-, or the carbon atoms of the benzene rings connecting with Y and Y may be directly combined to form a fluorine ring, and Z is CONH:

(in which -N(R1)2 is dimethylamino or piperidino) or (in which A is CH CH -CH or -CH(CH and R is H or alkyl of 1 to 2 carbon atoms), which are useful as psychotropic agents.

This invention relates to novel and therapeutically valuable N-substituted piperidine compounds of the formula jH-CHz-CHr-N 2 and pharmaceutically acceptable acid addition salts thereof, wherein Y is O, S or R is H, Cl, CH or OCH and Z is a-bivalent group'selected from the group consisting of in which R is OH, CN, com, COCZHS or cocii and R is dimethylamino, piperidino, morpholino, phenyl,

oracetylamino,

in which Q is O or S and'R is H, CH or phenyl.

The compounds of Formula I are produced by the following methods:

(a) By the reaction of a compound of the formula C H- CHr-CHa-X wherein X is a reactive atom or radical such as halogen, methylsulfonyloxy, phenylsulfonyloxy or tolylsulfonyloxy, with a compound of the formula 1 This reaction is usually carried out in a solvent, if necessary in the presence of a deacidfying agent and a condensation accelerator, usually at a temperature of 20 to 150 C. for a period of 5 to hours. The solvent may substituted phenyl (thesubstituent being Cl, CH or CF be water, methanol, ethanol, acetone, dioxane, tetrahyalkali metal iodide( e.g. NaI, KI).

(b) In order to produce the compounds of Formula I wherein Z is R being dimethylamino, piperidino or morpholino), by the reaction of a compound of the formula CHI Y (I with a cyanide of the formula Me-CN (V) wherein Me is hydrogen or alkali metal, with an amine of the formula HN--R (VI) This reaction is usually carried out in an inert solvent such as water, an alcohol (e.g. methanol, ethanol, propanol),'tetrahydrofuran, dioxane or a mixed solvent thereof at a temperature from room temperature to about the boiling point of the solvent employed for a period of 3 to 25 hours. Mostly, however, the reaction is preferably carried out in a solvent such as water, an alcohol or a mixed solvent thereof.

(0) .Inorder' to produce the compounds of Formula I wherein Z is (R being as defined above), by hydrolyzing a compound which is prepared by the method (b) mentioned above.

The hydrolysis is, for example, carried out by using a stoichiometrically 5 to 20 times molar quantity of 70% to sulfuric acid under heating at 60 to 95 C. for 30 minutes to 3 hours.

(d) In order to produce the compounds of Formula I wherein Z is (X being H, Cl, CH or CF3), by the reaction of a compound of Formula IV above with a Grignard reagent of the formula wherein Hal is halogen.

The reaction is carried out by the conventional manner adopted in the Grignard reaction, that is, by mixing acompound of Formula IV and a compound of Formula VII prepared from a phenyl or substituted phenyl halide and metallic magnesium in an inert solvent such as diethyl ether, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether or isopropyl ether, and then by heating the resulting'mixture at 20 C. to the boiling point of the solvent employed for 2 to 30 hours, and finally decomposing the reaction product with dilute acid or aqueous ammonium chloride solution. It is possible to use, if necessary, another solvent such as benzene, xylene, hexane or cyclohexane as the inert solvent.

3,770,729 .r a t 6 The starting compounds (H) and (IV) can be pro duced, for example, by the following methods:

O 7 0c x nai-M cmomcm-Nj 0cm cm-Y HO \C EX 7 J 2:; Halogen) cn,-Y

OC no CHICHICHIN: (IQIHX 00m Hose c R l cnr-Y CHCHaCHz-Hal CHr-Y Starting Compounds (11) OC CH-C r-N: a OCH: R1

\CH!Y/ [Hydrolysis Reference documents: H 0

Method (i)-Canadlan Patent 717, 977 and Chem. Ab. Vol. 64, 3443b CPI-C HPN 0 Method (ll)-J. Org. Chem. Vol. 27, 4134 (1962) R CH -Y Starting Compounds (IV) The compounds of Formula I can be converted into SUPPRESSION 0F SPONTANEOUS MOTILITY g i 'j Z g gg i 65 Suppression of spontaneous motility was measured by roc one, y ro romrc, su llIlC, nitric am or various organic acids (e.g. oxalic, maleic, fumaric, citric, tartaric, z i i g g m gg methansulfonic acid). 7 ourna o armaco 0gp, vo p. 6 (1953). e The compounds of Formula I and pharmaceutically acprocedure was as l w ceptable acidaddition salts thereof have excellent phar- 70 Each F Q conslstmg of five mlce (ddstram macological actions such as suppression of spontaneous mlce wglghmg to was kept a compartmentmotility and reserpine, potentiations as shown by the fol- Forty minutes after the intfaperitoneal administration of lowing t the test compounds, the spontaneous motility was counted The tests were carried out by the following proce- 20 mlmltes. The shOWs the dose required for dures: 50% suppression of spontaneous motility.

7 The results are shown in Table 1.

TABLE 1 Compound: ED (mg/kg. body weight) A 1.25-2.5 B 0.63-1.25 D 0.310.63 E 2.5-5.0 G 2.5-5.0 I

RESERPINE POTENTIATION Reserpine potentiation was measured by the method described by M. D. Aceto in Toxicology and Applied PharmacOlOgy, vol. 7, p. 329 ff. (1965). The procedure was as follows:

Thirty minutes after oral administration of the test compounds to female mice (dd-strain mice weighing 20 to 25 g., each group consisting of four mice), reserpine (l0 mg ./kg. of body weight) was injected intraperitoneally. The degree of blepharoptosisof both eyes was observed 15, 60, 120 and 180 minutes after the administration of reserpine.,The PD shows an efl ective dose potentiating the effect of reserpine by 30% minutes after the administration of reserpine.

The results are shown in Table 2.

In the above table, the test compounds (A, B, C, G) are as follows:

A: 11 [3 (4 carbamoyl 4 piperidino'piperidino)- propylidene] 6,11 dihydrodibenz[b,e]oxepin dihydrochloride /2 hydrate B: 11 [3 (4 hydroxy 4 phenylpiperidino)propylidene]-6,1 1-dihydrodibenz[b,e] oxepin hydrochloride C: 2 -chlor0 11 [3 (4 carbamoyl 4 piperidinopiperidino)propylidene] 6,11 dihydrodibenz[b,e] oxepin dihydrochloride /2 hydrate D: 11 [3 (4 hydroxy 4 p chlorophenylpiperidino)propy1idene] 6,11 dihydrodibenz[b,e]oxepin hydrochloride /2 hydrate v E: 1 l-[3- (4-carbamoyl-4-morpho1inopiperidino) pro- 3 ylidene]-6,l1-dihydrodibenz[b,e]oxepin dillydrochloride /2 hydrate F: 1 1 [3-(2,4-dioxo-3-methyl-1,3,8-triazaspiro [4.5] dec- 8-yl)propylidene]-6,ll-dihydrodibenz[b,e]hydrochloride I G: 11-[3-(1-thia-3-oxo-4,S-diazaspiro[4.5]dec-8-yl)propylidene]-6,1 1-dihydrodibenz[b,e] oxepin hydrochloride.

tional form such as tablets, capsules, powders, granules;

etc. 7

The following are the examples of the formulae tobe taken when the compound (I) of the present invention and acid addition salts are administered forthe pharmaceutical purpose.

(i) v 5 mg. and 25 mg. tablets are preparedfrom the following'compositions:

(ii) 10% powders are prepared from the following compositions:

Percent .Compound E -....I 10 Lactose 69 Starch 20 Methyl cellulose 1 Total r 100 The present invention will be better understood from the following examples, which are merely intended to be illustrative and; not limitative of the present invention.

. EXAMPLE 1 A mixture of 7.5 g. of 11-(3-bromopropylidene)-6,l1-

. 'dihydrodibenz[b,e]oxepin, 6 g. of 4-carbamoyl-4-piperidine, 4.9 g. of potassium carbonate, 30 ml. of toluene and 30 ml. of dimethylformamide is heated at ll2 C. with stirring for 6 hours. The cold water is added to the reaction mixture, the whole is extracted with toluene and washed withwat er. The toluene layer is extracted with dilute hydrochloric acid and the extract is made alkaline with potassium carbonate with cooling. The brown oil liberated is extracted with chloroform, the extract is dried and the chloroform is distilled off. The jellylike residue is dissolved in ethanol, and hydrogen chloride gas is introduced into the solution. The crystals precipitated are collected and refined from aqueous ethanol to give 11-[3-(4-carbamoyl 4 piperidinopiperidino)propylidene]-6,1l-dihydrodibenz[b,e]oxepin dihydrochloride /2 hydrate melting at 283 C. (decomposition).

EXAMPLE 2 A mixture of 7 g. of 11-(3-bromopropylidene)-6,ll-dihydrodibenz[b,e]oxepin, 5.1 g. of 4-hydroxy-4-phenylpiperidine, 4.6 g. of potassium carbonate, 30 ml. of toluene and 30 ml. of dimethylformamide is heated at 110-120 C: with stirring for 6 hours. After cooling, water is added EXAMPLES 3-26 f i Other ex mples of compounds (Dand acid addition salts thereof which'can be "pro'duced from a compound '(II) and a compound (III) in a manner similar to that described inExample 1 or 2 are shown in the following tables.

are as follows:

, 7 Salt and melting Example Y R Q R 1 point (0.) 23 O H S H H01, 290. 24,, O H --CH3 H01, 2122l5. 25 0 H S Malt=,ate,180181.

26 S H 0 CHa HCl, 183.

1 Decomposition.

EXAMPLE 27 A mixture of 6.6 g. of 11-[3-(4-ox0pipe1'idino)pr0- pylidene]-6,11-dihydr0dibenz[b,e]oxepin, 2.6 g. of potassium cyanide and 4.8 g. of piperidine hydrochloride in 10 ml. of water plus 40 ml. of ethanol is heated at. 70 C. with stirring for 24 hours. After cooling, the solvent is distilled ofi under vacuum, and the residue is dissolved in 100 m1. of toluene and washed with water. The toluene layer is dried over anhydrous magnesium sulfate, and then the toluene is distilled off. The jelly-like residue (crude 11 [3-(4-cyano 4 piperidinopiperidino)propylidene]-6,11-dihydrodibenz[b,e]oxepin, 7.2 g.) thus obtained is dissolved in 50 ml. of 85% sulfuric acid under heating. The solution is heated at 75 to 95 C. for an hour. After cooling, the solution is added onto 200 g. of ice and neutralized by an aqueous solution of sodium hydroxide. The oil liberated is extracted with toluene, the toluene layer is washed with' water, and dried, and the toluene is distilled off. The residue is dissolved in ethanol, and hydrogen chloride gas is introduced into the solution. The crystals precipitated are collected and refined from aqueous ethanol to give 3.7 g. of 1l-[3- (4-carbamoyl 4 piperidinopiperidino)propylidene]-6, 11-dihydrodibenz[b,e]oxepin dihydrochloride /2 hydrate melting at 283 C. (decomposition).

Proceeding by the method of Example 27,'but substituting equivalent amounts of appropriate starting ma terials (IV), (V) and (VI), the compoundsil) identical to the products of above Examples 1, 3-11 are also produced.

EXAMPLE 28 A soluion of 16 g. of 1l-[3- (4-oxopiperidino)propylidene]-6,11-dihydrodibenz[b,e]oxepin in 50 ml. of tetrahydrofuran is added at 10 to 20 C. to a solution of phenyl magnesium bromide in tetrahydrofuran prepared from 10.5 g. of phenyl bromide and 1.6 g. of metallic magnesium in 50 ml. of tetrahydrofuran. The resulting mixture is stirred at room temperature and then heated under reflux for 2.5 hours. After cooling, 100 mLof a'saturated ammonium chloride solution is added to the reaction mixture. The upper oil layer is extracted with toluene. The extract is washed with Water, dried and concentrated. The remaining oil is dissolved in benzene, and 30 ml. od about 5% hydrochloric acid is added to the solution. The

mixture is stirred to liberate a jelly-like hydrochloride. The benzene andwater phases are-removed by the decantation and the jelly-like residue is dissolved in chloroform. After drying, the chloroform is distilled ofi, a small amount of acetone isadded to the residue, and the whole is allowed to stand in a cold room. The crystals thus formed are collected and refined from aqueous acetone to give 12 g. of 11-[3-(4-hydroxy-4-phenylpiperidrochloride melting at 212-213 C.

Proceeding by the method of :Example 28, but substituting equivalentamounts-of appropriate starting materials (IV) and (VI1),.-the compounds (1) identical to the products of above Examples 2, 12-18 are also produced.

What is claimed is:

1. A compound selected from the. group consisting of a N-substituted piperidine compound of the formula:

CH O pylidene]-6,l1-diliydrodibenz[b,e]oxepin.

References Cited UNITED STATES PATENTS 3,527,766 9/1970 Protiva'et-al. 260-240 TC X 3,668,310 6/1972 Nakanishi etal. 260-29359 OTHER REFERENCES Starch et al.: Monatshefte fur Chemie, vol. 93, pp.

TOHN RANDOLPH, Primary Examiner US. Cl. X.I 

